Mechanistic studies on the regeneration of β-cells to balance the diabetic metabolic state in pancreas of LEW.1AR1-iddm rat and comparative in humans

通过T细胞抗体与抗促炎细胞因子特别是抗TNFα抗体的结合，首次建立了治疗人类1型糖尿病大鼠模型（IDDM大鼠）1型糖尿病的治疗概念。用这种方法治疗的大鼠血糖恢复正常。这项后续应用的目的是阐明内分泌胰腺中β细胞再生的潜在途径。分化的β细胞通过多种因素进入有丝分裂，从而通过增加增殖和抑制凋亡使β细胞质量正常化。DNA修复机制也通过将受损的β细胞转化为完整的细胞来促进再生。除了复制外，其他胰腺细胞类型也可以通过各种胰腺和β细胞特异性转录因子和增殖因子通过新生形成新的β细胞。随后的β细胞功能成熟过程由已知的（平顶）标记物和通过微阵列分析新发现的标记物介导。再生标记用多种方法在基因和蛋白质水平上进行检测。将非糖尿病大鼠、急性糖尿病大鼠和成功治疗的大鼠胰腺模型与不同形式的人、非糖尿病大鼠和糖尿病大鼠胰腺进行比较。这些关于β细胞再生的新发现旨在阐明治疗1型糖尿病的新成功治疗方法的机制。

By combining a T cell antibody with antibodies against proinflammatory cytokines, especially against TNFα, a therapy concept for curing type 1 diabetes in a rat model (IDDM rat) of human type 1 diabetes was established for the first time. The rats treated in this way became normoglycaemic again. The aim of this subsequent application is to clarify the underlying pathways of β-cell regeneration in the endocrine pancreas. Differentiated β-cells enter the mitotic division via various factors and thus normalize the β-cell mass by increasing the proliferation and inhibiting apoptosis. DNA repair mechanisms also contribute to regeneration by converting damaged β-cells into intact ones. In addition to replication, new β-cells can also be formed from other pancreatic cell types via various pancreatic and β-cell specific transcription factors and proliferation factors via neogenesis. The subsequent process of functional maturation of the β-cells is mediated by known (flattop) markers and newly discovered makers by microarray analysis. The regeneration markers are examined using a variety of methods at the gene and protein level. The results are collected in the rat model in non-diabetic, acutely diabetic and successfully treated pancreata compared to human, non-diabetic and diabetic pancreata of different forms. These new findings on β-cell regeneration are intended to clarify the mechanisms on which the new successful therapeutic approaches for curing type 1 diabetes are based.